The overall goal of this MERIT review grant application is to characterize polyphenols as potential prophylactic as well as therapeutic agents in veterans with depression. The proposed studies have important implications for the veteran population since approximately 30% of veterans, in particular those from Operation Enduring Freedom/Operation Iraqi Freedom, are affected by mood anxiety disorders, especially depression. We recently identified a safe and well-tolerated bioactive polyphenol preparation effective in delivering multiple (16 that we identified) bioavailable polyphenol metabolites to the brain. Moreover, we found that oral supplementation with this preparation significantly promotes resilience to depression/anxiety phenotypes in the repeated social defeat stress (RSDS) mouse model of depression. Synaptic plasticity abnormalities in nucleus accumbens (NAc) medium spiny neurons (MSN) play a key role in the development of stress-related depression/anxiety. Our proposed studies are designed to identify select polyphenol metabolites that can preserve synaptic plasticity in vitro i primary NAc MSN-enriched cultures and in vivo in the RSDS model. Our evidence indicates that down-regulation of Rac1 (a GTPase-related protein that controls actin remodeling) in NAc MSNs is central to aberrant synaptic remodeling in depression/anxiety, and that resilience to depression/anxiety may also be augmented by attenuation of excitatory VGLUT2 and/or promotion of inhibitory VGAT MSN synaptic mechanisms. Based on this evidence, in the proposed studies, we will first screen individual polyphenol metabolites for their in vitro dose-response bioactivities in modulating Rac1, VGLUT2, and VGAT in MSN- enriched cultures. Based on the outcomes of the in vitro screening, we will then prioritize the three most bioactive candidates and conduct dose-finding studies in vivo using polyphenol precursors as potential pro- drugs able to deliver the identified metabolites to the brain. Based on the outcomes of this set of studies, we will identify the lowest safe and efficacious doses of polyphenol precursors with sufficient concentration to engage the molecular targets (e.g. Rac1) in the NAc. In efficacy studies, we will then test whether these brain bioavailable bioactive metabolites delivered through precursors may promote resilience to stress-induced depression/anxiety phenotypes by normalizing stress-induced pathological neuroplasticity remodeling and functional electrophysiological changes in the NAc. Collectively, the outcomes from our proposed studies will identify novel prophylactic as well as therapeutic agents that can prevent and reverse the maladaptive behavioral responses that result from chronic stress. The proposed studies will also provide novel mechanisms underlying the beneficial role of polyphenols on stress-mediated depression. The proposed studies will provide the impetus for translational application of safe polyphenol pro-drugs to promote psychological resilience to stress-related conditions, including depression and anxiety disorders in veterans.